Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review

Abstract Introduction Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0–19 years. Methods Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009–March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post‐treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. Results and discussion In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single‐arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single‐arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second‐ or subsequent‐line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second‐ or subsequent‐line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0–50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. Conclusions These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer‐term outcomes, such as weight and metabolic changes.


I N T R O D U C T I O N
In 2020, approximately 1.7 million children aged 0-14 years were living with HIV worldwide [1]. The World Health Organization (WHO) recommends that all children and adolescents living with HIV start antiretroviral ther-apy (ART) regardless of CD4 cell count or disease stage [2]. Since treatment is life-long, optimizing therapeutic regimens to maximize effectiveness and tolerability, and minimize side effects is critical to achieving the durability of treatment and favourable health outcomes in children and adolescents.
Dolutegravir is an integrase strand transfer inhibitor (integrase inhibitor) that has a high genetic barrier to developing HIV drug resistance, and few drug-drug interactions compared with other antiretrovirals [3,4]. Dolutegravir is a key component of first-line and second-line treatment for adults living with HIV and is also recommended as the preferred option for all children aged ≥4 weeks and weighing ≥3 kg [5]. Another integrase inhibitor, raltegravir, is approved for use from birth in full-term neonates weighing ≥2 kg and is recommended as the preferred regimen for neonates, and the alternative integrase inhibitor regimen for infants aged ≥4 weeks [5,6]. Two other integrase inhibitors, elvitegravir and bictegravir, are approved for paediatric use in fixed-dose formulations, but these are not currently recommended by WHO.
Despite the documented benefits of integrase inhibitors, sleep disorders have been reported in adults on dolutegravir, and there are questions around weight gain in adults on dolutegravir or raltegravir [7][8][9]. With the widespread adoption of integrase inhibitor-based regimens for first-line and subsequent lines of treatment, monitoring short-and longterm health outcomes is critical. As new paediatric formulations of dolutegravir become available, it is particularly important to establish ongoing effectiveness and safety in realworld clinical settings in younger populations. To date, no systematic reviews have summarized the use of integrase inhibitors in children and adolescents. We conducted this systematic review on the effectiveness and safety of dolutegravir and raltegravir in neonates, infants, children and adolescents to support the development of the 2021 WHO consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring [5], and to inform the prioritization of future optimal drug formulations for children and adolescents [10].

M E T H O D S
This systematic review followed Centre for Reviews and Dissemination guidance [11], and is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [12] (PROSPERO number CRD42020204432) [13]. The review was developed to assess five drugs: dolutegravir, raltegravir, darunavir, lopinavir (solid formulations) and tenofovir alafenamide. This paper presents the results pertaining to dolutegravir and raltegravir.

Data sources and search strategies
Searches were run in MEDLINE, MEDLINE In-Process, MED-LINE E-pub ahead of print (via Ovid), Embase (via Ovid) and The Cochrane Library using both free-text terms and index terms (File S1). Grey literature searches involved handscreening of reference lists from all included studies and HIV treatment guidelines, and searches of clinical trial registries. Additionally, databases of abstracts from selected conferences occurring January 2018-March 2021 were searched (File S1). English-or French-language publications were eligible if they reported on children and/or adolescents living with HIV aged 0-19 years, receiving dolutegravir or raltegravir for firstline or subsequent-line of therapy (Table 1). Studies were only included if they presented results stratified by drug, or if at least 80% of the treatment group were on one of the two drugs, and if they reported efficacy or effectiveness and/or safety outcomes through 6 months post-treatment initiation. Where eligibility of a study was unclear, authors were contacted for more information. Observational studies and clinical trials published between 1 January 2009 (before first approval date for use of the drugs in children and adolescents) and 21 March 2021 were included. Case studies, letters and reviews were excluded. The following studies were also excluded: those reporting outcomes in infants exposed to HIV in utero or through breastfeeding (where the drugs were used for prophylaxis rather than treatment); those reporting only pharmacokinetic parameters or drug-drug interactions; and those reporting only on adult populations aged ≥18 years and/or pregnant women.

Article screening and data extraction
All articles (abstracts and papers) were screened in duplicate against the eligibility criteria by three reviewers (JOR, CT and EM), and results were recorded by each reviewer independently. Disagreements were resolved by discussion and with other members of the project team where necessary. Data from selected articles were extracted into a standard Microsoft Excel form by a single reviewer. Extracted data were independently checked by a second reviewer. Likewise, risk of bias was assessed and recorded by one reviewer and checked by a second reviewer, using the Cochrane Risk of Bias Tool (Version 2) for randomized controlled trials (RCTs), the National Institutes of Health quality assessment tool for non-randomized interventional studies and the CLARITY tool for cohort studies. The list of questions for each tool is presented in Table 2 . Data on study characteristics, subject characteristics, efficacy/effectiveness and safety were extracted ( Table 1). The primary outcomes were CD4 counts, HIV RNA viral load, mortality, grade 3/4 adverse events and treatment discontinuation. Additional outcomes are listed in File S1. For binary and categorical outcomes, number and proportion of subjects with the event were extracted, or estimated using available data, while for continuous outcomes, mean, median, range, interquartile range (IQR), change from baseline (start of study drug), regression coefficients and 95% confidence intervals (CI) were extracted. Data reported in figures only were extracted using the online tool "Web Plot Digitizer" [14].

Definitions
Infants were defined as <12 months old, children as 1 to under 12 years old and adolescents as 12-19 years old (in line with age categories used in identified studies). Subjects were defined as being on second-or subsequent-line of ART if they had previously received regimens containing drugs other than dolutegravir or raltegravir, regardless of the reason for switching regimens; switching of dose or formulation only was not considered a change of treatment line. Treatment line was described as "mixed" if a study included subjects on first-and subsequent-line ART and data were not stratified. Adverse events reported as grade 3 (severe) or grade 4 (life threatening or disabling) according to standard definitions [15] were recorded and could be due to clinical signs or symptoms, or laboratory findings. We report the number of subjects who experienced at least one grade 3 or 4 adverse event, rather than the total number of events. Grades 1 and 2 events were not extracted, nor were "serious adverse events," unless the grade of event was reported. Studies defined as cohort studies included prospective and retrospective observational studies and chart reviews. Studies are referred to by their name, where provided, and otherwise by first author and year of publication.

Evidence synthesis
For most outcomes, the proportion of subjects experiencing each outcome was presented. Scatterplots showing viral suppression were generated in Stata version 16, and safety outcomes were presented as heatmaps developed in Microsoft Excel.

Deviations from the protocol
Following publication of the protocol on PROSPERO, we added an additional risk of bias tool to assess non-randomized interventional studies (discussed above). We also added an additional outcome of interest: changes in lipid variables (cholesterol and triglycerides) from baseline.

Study selection
The searches for the review were conducted on 12 August 2020 and rerun on 21 March 2021 to capture studies published subsequently. Results of the searches and screening are presented in a PRISMA flow diagram ( Figure 1). Overall, 3626 abstracts and 371 papers were screened. Nineteen studies relating to dolutegravir and/or raltegravir were included. These studies were published in 17 papers and 14 conference presentations; two studies reported data for both dolutegravir and raltegravir [16,17]. Screening of trial registries identified 13 studies assessing dolutegravir and three assessing raltegravir that were either ongoing or completed, but with no published results identified in this review (File S2, Table S1).

Study and subject characteristics
Eleven studies reported data on dolutegravir, with median follow-up duration of 6-36 months: one RCT [18], one singlearm trial [19] and nine observational studies [16,17,[20][21][22][23][24][25][26][27] ( Table 3). Six studies recruited subjects from Europe only, three from sub-Saharan Africa only and two from multiple geographic regions (Table 3). Of note, three studies included subjects being treated at the same hospital [20][21][22]; as the study time periods overlapped, some individuals may have been included in more than one study. In addition, we identified two sub-studies of ODYSSEY assessing safety and pharmacokinetic outcomes in children and adolescents with and without tuberculosis [28,29]. We included results from these sub-studies if the studies reported safety outcomes not presented for the main trial. Across the studies, 2330 children received dolutegravirbased therapy (Table 3). Nine studies included children and adolescents, one study also reported data on infants [30] and two studies included adolescents only [20,23]. Most studies included subjects in the target age range, but in Briand 2017, a quarter of subjects were over 20 years of age (median, 18.0 years, IQR 15.6-20.2) and were included within the results presented here [20]. Five studies included a small proportion of subjects (<15%) receiving dolutegravir as first-line therapy, but none reported stratified safety data for first-line treatment. One study included only subjects who were virally suppressed at baseline [24], four included a population with mixed viral load levels, three included subjects who were not suppressed and three did not report suppression at baseline (Table 3).

Risk of bias
Results of the risk of bias assessment are shown in Figure 2, with additional details described in Table 4. Risk of bias for the ODYSSEY RCT was rated as low [18]. The single-arm trial was deemed to be of unclear risk of bias ( Figure 2 and Table 4) [19]. Of the nine observational studies, four were rated as high risk of bias [21,24,26,27], two as unclear [20,22] and three as low risk [21,24,26] (Figure 2 and Table 4).

Safety outcomes
Mortality. Four studies reported all-cause mortality in subjects on dolutegravir [18-20, 22, 30-32] (Figure 4). In ODYSSEY, there were two deaths (0.6%) in the dolutegravir arm, and three (0.8%) in the standard of care arm over Single-arm trial Unclear Uncertainty around whether all eligible participants were enrolled and whether the study was sufficiently powered; no sample size calculation reported. ANRS EPF-CO10 [21] Observational study High Study was not designed to assess dolutegravir alone; viral load and other key prognostic factors not reported at baseline. Giacomet 2020 [23] Observational study Unclear Conference poster with limited methodological data provided. Thivalapill 2020 [24,50] Observational study High Study excluded subjects who had viral load >200 copies/ml at any time during the study; although study only reported safety data, it is possible that key safety events were missed. Bacha 2020 [25] Observational study Unclear Conference poster-median duration of follow-up not provided but study took place over 10 months, so median time on treatment may be less than 6 months. median follow-up of 142 weeks [18]. One of the deaths in the dolutegravir arm was due to tuberculosis-related causes [29]. In IMPAACT P1093, one child (2%) in a population of infants and children (4 weeks to 6 years; n = 51) died of acute gastroenteritis dehydration during 24 weeks of followup (not considered related to dolutegravir) [30]. No deaths were reported in the remaining two cohort studies [20,22].  [28]. In one study, total number of events was reported, but number of subjects was unclear: seven events were reported in 23 children aged 6 to <12 years in IMPAACT P1093 [32] (data not included in Figure 4). Across the studies, three grade 3/4 neurological or psychiatric events were reported: two in Briand 2017 (Table 5) and one in IMPAACT P1093 (depression and attempted suicide in a subject with a pre-existing mental disorder) [31]. Three grade 3/4 events were considered possibly related to dolutegravir in two of six studies reporting drug-related grade 3/4 adverse events (Figure 4 and Table 5) [16,17,20,22,27,28,[30][31][32]. Two were reported in Briand 2017 [20] and one in Abo 2019, which did not report overall grade 3/4 adverse events (Table 5) [16]. Discontinuations due to adverse events. Data on discontinuations for adverse events of any grade were reported in six studies (Table 3). No events were observed in three studies , or <400 copies/ml, <1000 copies/ml or viral suppression at an unspecified threshold if <50 copies/ml was not reported (shaded symbols) after treatment with (a) dolutegravir or (b) raltegravir over time. Results are stratified by age (colour of symbol), line of therapy (shape of symbol) and study size (size of symbol). Connecting lines link data follow-up points from the same study population. Data from an individual study may be presented at more than one timepoint; however, at a given timepoint, data from a group of subjects are only presented once (overall data were prioritized over sub-group data). For randomized controlled trials and single-arm studies, the timepoint represents the duration of follow-up; for observational studies, the timepoint represents the median follow-up time of the study. A table showing the viral load data used to create the scatterplot is included in File S2 (Table S2).
(follow-up to 144 weeks in IMPAACT P1093, 24 weeks in ODYSSEY pharmacokinetic sub-study and up to 43 weeks in Bacha 2020) [19,25,28,30,31] (Figure 4). One discontinuation (2%) due to a grade 3/4 adverse event was reported during a median of 40 weeks of treatment in Briand 2017 (Table 5), while one adolescent (2%) discontinued treatment due to dizziness and sleep disturbance (grade not reported) in Frange 2019 [20,22]. In Abo 2019, five subjects (17%) discontinued dolutegravir over a median of 62 weeks due to adverse events (mood deterioration, sleep disturbance and raised creatine kinase, raised gamma-glutamyl transferase, abdominal pain and hypertension; grades not reported) [16]. Other outcomes. Limited data on growth and lipid levels were reported. Thivalapill 2020 reported a mean height for age Zscore (HAZ) of -0.1 (95% CI -0.1, 0) after more than 26 weeks of follow-up among 460 adolescents on dolutegravir [24]. The HAZ rate change was -0.1 (95% CI -0.1, 0; p<0.01) per year after dolutegravir initiation, while the rate of change in weight for age Z-score (WAZ) was 0.2 per year (95% CI 0.2, 0.3; p<0.001); however, subjects were only followed up for up to 1 year, and the study was considered high risk of bias.
Total cholesterol data in children and adolescents were reported in ODYSSEY, comparing dolutegravir (n = 350) to standard of care (n = 357; 92% of subjects on first-line therapy received efavirenz, and among those on second-line therapy, 72% received ritonavir-boosted lopinavir and 25% ritonavir-boosted atazanavir) [18]. After 48 weeks of treatment, total cholesterol decreased with dolutegravir treatment (mean change from baseline: -5 mg/dl, 95% CI -8, -3) and increased with standard of care (+10 mg/dl, 95% CI +7, +13). After 144 weeks, mean change was -2 mg/dl (95% CI -7, +2) in the dolutegravir arm and +11 mg/dl (95% CI +6, +16) in the standard of care arm. Similarly, in Giacomet 2020, mean total cholesterol decreased from 190 mg/dl at baseline to 168 mg/dl in 14 adolescents on dolutegravir for 52 weeks (p = 0.0057) [23]. A significant difference was also reported for low-density lipoprotein cholesterol (decrease from 109 to 96 mg/dl; p = 0.025), but the change was not significant for highdensity lipoprotein. Figure 4. Proportion of subjects exposed to dolutegravir or raltegravir with reported safety outcomes, ordered by study, sub-population (age or weight group) and timepoint (median follow-up time for observational studies and ODYSSEY pharmacokinetic sub-study; duration of follow-up for other studies). Multiple rows for the same study correspond to different sub-populations and/or timepoints (further details are provided in File S2, Table S6); subjects or events may, therefore, appear in more than one row. Numbers in coloured cells correspond to the number of subjects who experienced events. Where data are reported for grade 3/4 clinical adverse events and for grade 3/4 laboratory adverse events but not for all grade 3/4 adverse events, this is because overlap between clinical and laboratory events was unclear or not reported. * Subjects in the ODYSSEY pharmacokinetic sub-study were also included in the main trial; results

Risk of bias
The REALITY RCT and the single-arm trial, IMPAACT P1066, were classified as low risk of bias across all domains of the relevant risk of bias tools ( Figure 2) [34,35]. Among observational studies, CHIPS was deemed high risk of bias (Table 4) [17].

Safety outcomes
Mortality. Six studies (one RCT, one single-arm trial and four observational studies) reported on mortality in subjects on raltegravir ( Figure 4) [34-36, 38, 39, 41-43]. The REAL-ITY trial reported mortality data for children and adolescents on a first-line raltegravir-intensified regimen (nevirapine or efavirenz-based regimen, plus raltegravir) for 12 weeks with 24 weeks of follow-up [34]. There was one death (3%) in the raltegravir-intensified ART arm compared with two (6%) in the standard ART arm (nevirapine or efavirenz-based regimen) (hazard ratio 0.43, 95% CI 0.04, 4.70, p = 0.74). Two deaths in subjects on second-or subsequent-line raltegravir were reported in IMPAACT P1066 ( Figure 4) [42,43]. In the cohort of infants and children (6 months to <2 years; n = 14) followed up for 48 weeks in IMPAACT P1066, one child with multiple co-morbidities died of gastroenteritis, but this was not considered related to raltegravir [42]. In children aged 2-12 years (n = 33) receiving raltegravir chewable tablets, one child died of gastroenteritis at week 59 of 240 weeks of follow-up [43]. In addition, a teenage girl died from pneumonia in IMPAACT P1066, but the death was not included in the final analysis, as the subject was not on the final selected dose of raltegravir. One death (2%) was reported in a child in the IeDEA global consortium (n = 62) during 104 weeks of follow-up [39].

Summary of findings and implications for research
Findings from this systematic review suggest that dolutegravir and raltegravir are safe and effective in infants, children and adolescents living with HIV. Across dolutegravir studies, effi-cacy/effectiveness was high, with only three datapoints (of 21 datapoints from eight studies) showing viral suppression in less than 60% of the study population; all three were studies with small sample sizes (<25). However, there were limited data in infants and young children and few data on longterm effectiveness beyond 2 years. The majority of data were from studies assessing second-, subsequent-or mixed-lines of therapy, although initial, limited data suggest that dolutegravir is effective for first-line treatment. Although viral suppression data from ODYSSEY were not available at the time of this review, this trial has since published results through 96 weeks. For first-line treatment, viral load <50 copies/ml was reported in 80% (117/146) of participants in the dolutegravir arm and 81% (113/140) in the standard of care arm, while for second-line treatment, 81% (153/196) of participants in the dolutegravir arm and 72% (139/200) in the standard of care arm were virally suppressed at 96 weeks [44]. In most raltegravir studies, over 50% of subjects achieved viral suppression at 24 and 48 weeks. In long-term follow-up (≥144 weeks), the proportion of children and adolescents with viral suppression ranged from 30% to 63%. However, there were limited data on raltegravir as first-line therapy and limited data in infants. Importantly, five of seven raltegravir studies reporting viral suppression data included heavily pre-treated subjects, which may explain why lower proportions of subjects achieved viral suppression compared with studies of dolutegravir. As raltegravir is now recommended in infants and young children as an alternative first-line treatment, opportunities to monitor effectiveness and safety in this population group should be sought.
Few deaths were reported across the studies on dolutegravir and raltegravir, and none were due to adverse events related to either drug. Although the proportion of subjects with clinical and/or laboratory grade 3/4 adverse events ranged from 0% to nearly 50% across the studies, few events were considered drug related (<10%), and there were few discontinuations for adverse events of any grade (range 0-17%). The highest proportions of grade 3/4 adverse events were reported in the IMPAACT P1066 and IMPAACT P1093 trials, which recruited subjects with high viral loads, many of whom had extensive treatment experience. This review also highlighted the need for further safety data in infants, who were included only in registrational trials [30,42]. ODYSSEY has since presented data showing no safety concerns for children weighing <14 kg treated with dolutegravir (median follow-up 120 weeks) [45]. Two single-arm trials assessing raltegravir in infant populations were identified through searches of trial registries, with planned completion dates in 2019 and 2031 (IMPAACT P1115/NCT02140255 and IMPAACT P1101/NCT01751568). There were also limited data on weight gain in children and adolescents on dolutegravir or raltegravir, although the ODYSSEY trial recently published additional data, showing improved growth with no excess weight gain in children and adolescents on dolutegravir, compared with standard of care [46]. The randomized trial, SMILE, identified via trial registry searches, pre-specified weight as an outcome and also presented data recently, which showed significant increases in weight and body mass index at 48 weeks in children on an integrase inhibitor plus boosted darunavir compared with standard of care [47].

Strengths and limitations
To our knowledge, this is the first systematic review on efficacy/effectiveness and safety of dolutegravir and raltegravir in infants, children and adolescents. Although we did not conduct any meta-analyses, this narrative review summarizes the current evidence-base and provides reassurance to support the expanding rollout of dolutegravir-based regimens. Many of the studies identified had relatively small sample sizes, of less than 100 subjects, which might explain some of the variability in the proportions of subjects experiencing adverse outcomes. Variability could also be explained by differences in reporting of adverse events between observational studies and clinical trials; furthermore, not all studies clearly stated the grading standards used for recording adverse events. For pragmatic reasons, we restricted our searches to English and French publications, but we recognize that this could cause language bias in the results of our review. Many of the studies identified were observational and, therefore, have more potential sources of bias than RCTs or single-arm studies. In this review, four of the 15 observational studies were rated high risk of bias and five as unclear risk. However, such studies remain important in providing realworld data from different clinical settings. Data on longerterm outcomes of these new drugs and formulations are critical. This review identified a wide range of studies with disparate research questions. Some studies reported outcomes which may have been of clinical or scientific interest but are not reported here as they were not comparable to the results of other studies.

C O N C L U S I O N S
In this review, dolutegravir and raltegravir were found to be safe and effective across the studies identified. These findings support the current WHO treatment guidelines, which recommend a dolutegravir-based regimen for first-line treatment of HIV in children and adolescents, and a raltegravirbased regimen in neonates for whom dolutegravir dosing is not yet approved [5]. However, long-term monitoring of the use of integrase inhibitors in paediatric populations will be important to fill evidence gaps, particularly for adverse outcomes reported in adult studies, including metabolic and neuropsychiatric outcomes, and in relation to their use in infants, and in first-line regimens.

C O M P E T I N G I N T E R E S T S
AJ and IJC were authors on the two Collaborative HIV Paediatric Study (CHIPS) publications included in the review [17,27]. AJ and IJC report recent grant funding from ViiV Healthcare/GSK, which is the marketing authorization holder for Tivicay (dolutegravir). There were no other competing interests.

A U T H O R S ' C O N T R I B U T I O N S
CLT, JOR, EM, IJC, AJ, MV, JJ, VL, FR and MP contributed to developing the study protocol. JOR conducted the searches. JOR, CLT and EM contributed to screening of abstracts and papers, extracted the data from selected studies and assessed the studies for risk of bias. CLT and JOR drafted the paper. JOR, CLT and HC developed the figures. All authors reviewed the manuscript and approved the final draft.

A C K N O W L E D G E M E N T S
Thank you to Deborah Ford, ODYSSEY trial statistician, who reviewed the results presented from ODYSSEY in a draft manuscript.

F U N D I N G
This work was supported by the World Health Organization and the International AIDS Society's Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Prospero number CRD42020204432.

D I S C L A I M E R
The opinions expressed here are those of the authors and do not necessarily reflect the views of the funder. All authors had full access to all the data in the study, and the corresponding author had final responsibility for the decision to submit for publication.

D ATA AVA I L A B I L I T Y S TAT E M E N T
The data extracted for this systematic review are available within the article and its supplementary materials.

R E F E R E N C E S S U P P O R T I N G I N F O R M AT I O N
Additional information may be found under the Supporting Information tab for this article: File S1. Details of data sources, search strategies and data extracted. File S2. Supplementary tables. Table S1. Study characteristics of clinical trials on dolutegravir or raltegravir in infants, children and/or adolescents identified through searching of registries, March 2021, for which no publications were identified at the time of the searches. Table S2. Viral load data used to create the scatterplots presented in the paper (Figure 3). Table S3. Treatment failure data from ODYSSEY. Table S4. CD4 cell count or percent at baseline in studies in which data on change in CD4 measurement from baseline were also reported. Table S5. Change in mean or median CD4 cell count or CD4 percent from baseline. Table S6. Details of population sub-groups presented in Figure 4 (age-bands, weight groups and dose/formulations).